CN115316960B - Brain nerve activity regulation and control and brain information synchronous reading system - Google Patents
Brain nerve activity regulation and control and brain information synchronous reading system Download PDFInfo
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- CN115316960B CN115316960B CN202211254143.6A CN202211254143A CN115316960B CN 115316960 B CN115316960 B CN 115316960B CN 202211254143 A CN202211254143 A CN 202211254143A CN 115316960 B CN115316960 B CN 115316960B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
- A61B5/004—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
- A61B5/0042—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part for the brain
Abstract
The invention discloses a brain nerve activity regulation and control and brain information synchronous reading system. The recording light source module emits imaging light beams through the imaging light source and passes through the stimulation module; the stimulation module emits a stimulation light beam through a stimulation light source; the signal acquisition module receives the imaging light beam and the stimulating light beam, inputs the imaging light beam and the stimulating light beam to neurons of a brain region of an organism by using the implanted multimode optical fiber, regulates and controls the brain nerve activity of the organism and excites the neurons to generate signals, acquires fluorescence and returns the fluorescence to be sent to the signal recording module; the signal recording module receives the fluorescence and converts the fluorescence into an electric signal. The invention can realize single recording function, single stimulation function and recording stimulation synchronization function, realize different experimental paradigms, ensure the stability of the system, effectively avoid the influence of high-power stimulation light on imaging light and measuring signal light, and has the advantages of compatibility of experimental organisms, magnetic compatibility, synchronous stimulation and recording and adjustable stimulation parameters.
Description
Technical Field
The invention relates to a synchronous detection system for brain neural activity of an organism, in particular to a system for regulating brain neural activity and synchronously reading brain information.
Background
The mammalian brain is divided into a plurality of different brain areas according to functional similarity, each brain area corresponds to different types of neural information, and understanding of the functions of each brain area of the brain needs to be based on certain control and recording technology. Through the accurate regulation and control of the specific brain areas of the freely moving animals and the recording of the corresponding nerve activities, the functions of all the brain areas can be better understood, the function information of the related brain areas in specific behaviors is provided, and important data and theoretical support are provided for further understanding and treating related diseases.
Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) enable observation of neuronal activity at the whole brain level caused by various external stimuli. However, such observation means based on the whole brain lacks accurate spatial resolution and temporal resolution, and is difficult to be applied to the research of real-time brain functions of freely moving organisms, and cannot distinguish brain regions. The electrophysiological technology utilizes energy such as electricity, sound and the like to stimulate organisms, records electric phenomena generated by the organisms through metal or glass electrodes implanted into the bodies, and has single cell scale and high time precision. However, electrode recording is susceptible to electromagnetic and motion interference, cannot be recorded for long periods of time, and cannot achieve synchronization of stimulation and recording sites. The neuron activity releases a large amount of calcium ions, so that the action potential of the neuron can be tracked through calcium imaging to know the activity of a neuron cluster. Due to the highly scattering and highly absorbing properties of biological tissues, conventional optical stimulation and calcium imaging methods (such as confocal and two-photon) cannot cover the deeper (> 1 mm) region below the cerebral cortex. The optical fiber recording technology provides a free-behavior biological nerve activity reading and recording scheme by utilizing the excellent light guiding capacity of the optical fiber. The optical fiber probe has small volume, good flexibility and high sensitivity, and can read and record the nerve activity condition of the related brain area for a long time.
The existing optical fiber recording system cannot be compatible with the optical stimulation regulation and control module, and an additional optical fiber needs to be introduced to realize the optical stimulation regulation and control function, so that the difference between a regulation and control site and a signal reading site is caused.
Disclosure of Invention
In order to solve the problems in the background art, the invention provides a brain nerve activity regulation and control and brain information synchronous reading system, which can introduce light stimulation regulation and control on the basis of ensuring the signal reading precision and realize the light stimulation regulation and control of a single optical fiber and the synchronous reading of brain information. The invention has the advantages of compatibility of experimental organisms, synchronous photostimulation regulation and control and signal reading and recording, and adjustable stimulation parameters.
The technical scheme adopted by the invention is as follows:
the device comprises a recording light source module, a signal acquisition module and a data processing module, wherein an imaging light beam emitted by an imaging light source passes through a stimulation module and then reaches the signal acquisition module;
the stimulation module sends out stimulation light beams to the signal acquisition module through a stimulation light source;
the device comprises a signal acquisition module, a light source module and a control module, wherein the signal acquisition module is used for receiving imaging light beams from the recording light source module and stimulating light beams from the stimulating module, inputting the imaging light beams and the stimulating light beams to neurons of a brain region of an organism by using an implanted multimode optical fiber, regulating and controlling the brain nerve activity of the organism and exciting the neurons to generate signals, and realizing real-time acquisition of brain region nerve signals of the organism and monitoring of the light source; meanwhile, the multimode optical fiber is used for collecting fluorescence generated after the imaging light beam irradiates the neuron and returning the fluorescence to the signal recording module; and coupling regulation is carried out on the imaging light beam and the stimulating light beam.
The fluorescent light detector comprises a signal recording module, and the fluorescent light from the signal acquisition module is received and converted into an electric signal.
The imaging light source emits imaging light beams with the central wavelength of 473 nanometers, and the stimulating light source emits stimulating light beams with the central wavelength of 589 nanometers.
The recording light source module comprises an imaging light source, a second half-wave plate, a second scanning galvanometer, a third double-cemented lens, a first reflecting mirror, a fourth double-cemented lens and a second reflecting mirror; the imaging light source, the second half-wave plate and the second scanning galvanometer are sequentially arranged along the same linear optical axis, the second scanning galvanometer, the third double-cemented lens and the first reflector are sequentially arranged along the same linear optical axis, and the first reflector, the fourth double-cemented lens and the second reflector are sequentially arranged along the same linear optical axis; the imaging light source emits imaging light beams, the imaging light beams are subjected to polarization rotation of the second half-wave plate and reflection of the second scanning galvanometer in sequence, then are transmitted through the third double-cemented lens, reflected by the first reflecting mirror, transmitted through the fourth double-cemented lens and reflected by the second reflecting mirror in sequence, then are incident into the polarization beam splitter prism, and are incident into the signal acquisition module after being reflected by the polarization beam splitter prism.
The stimulation module comprises a stimulation light source, a first half-wave plate, a first doublet lens, a second doublet lens, a first scanning galvanometer, a scanning mirror, an infinite far correction sleeve lens and a polarization beam splitter prism; the laser source, the first half-wave plate, the first doublet lens, the second doublet lens and the first scanning vibration mirror are sequentially arranged along the same linear optical axis, the laser source emits stimulating light beams, the stimulating light beams are sequentially subjected to polarization rotation through the first half-wave plate, beam expanding and collimation through a doublet lens component formed by the first doublet lens and the second doublet lens, are reflected by the first scanning vibration mirror, are transmitted through the scanning mirror and the infinity correction sleeve lens in sequence, are incident into the polarization beam splitter prism, and are incident into the signal acquisition module after being transmitted through the polarization beam splitter prism.
The signal acquisition module comprises a dichroic mirror, an objective lens, a first multimode optical fiber, a self-calibration module and a photoelectric detector; the two output ends of the self-calibration module are respectively connected with a photoelectric detector and neurons in a brain region of an organism, and the stimulating light beams and the imaging light beams after transmission are respectively incident to the photoelectric detector and the neurons in a brain region of the organism through the self-calibration module;
the self-calibration component comprises a 1x2 fused fiber coupler, a second multimode fiber and a third multimode fiber; one bundling end of the 1x2 fused fiber coupler is used as an input end of the self-calibration component and connected with the other end of the first multimode fiber, and two branch ends of the 1x2 fused fiber coupler are respectively connected with the photoelectric detector and neurons of the brain region of the organism through the second multimode fiber and the third multimode fiber.
The signal recording module comprises an optical filter, a fifth double-cemented lens and a camera; the optical filter, the fifth double-cemented lens and the camera are sequentially arranged along the same straight line optical axis, and the fluorescence coming from the signal acquisition module is incident into the camera after being filtered by the optical filter and converged by the fifth double-cemented lens in sequence and is detected and acquired by the camera.
The fiber end faces of the first multimode fiber, the second multimode fiber and the third multimode fiber are designed with 8-degree inclined planes and added with optical coatings.
The vibration mirror controller is electrically connected with the second scanning vibration mirror of the recording light source module, the first scanning vibration mirror of the stimulation module and the photoelectric detector of the signal acquisition module respectively, collects an electric signal detected by the photoelectric detector in real time and performs feedback adjustment on the work of the second scanning vibration mirror of the recording light source module and the first scanning vibration mirror of the stimulation module. Finally, the imaging light beam and the stimulating light beam are coupled and regulated.
The optical axis of an objective lens perpendicular to the signal acquisition module is used as a detection surface, and the x direction and the y direction which are perpendicular and orthogonal to each other are established on the detection surface:
the first scanning galvanometer adjusts the x direction and is used for deflecting the stimulating laser beam in the x direction to realize light stimulation with different frequencies and time;
and the second scanning galvanometer adjusts the x direction and the y direction and is used for deflecting the thorn laser beam in the x direction and the y direction to realize optical imaging.
The on and off switching of the first scanning galvanometer is combined with the on and off switching of the second scanning galvanometer in two different states to construct three different modes of the system:
mode one, single recording mode
Controlling the first scanning galvanometer to be in an off state and the second scanning galvanometer to be in an on state, controlling the photoelectric detector to sample at intervals to obtain a light intensity signal with lower intensity of an imaging light beam, and keeping a camera to continuously acquire images in real time;
mode two, single stimulation mode
Controlling the first scanning galvanometer to be in a state on and the second scanning galvanometer to be in a state off, controlling the photoelectric detector to sample at intervals to obtain a light intensity signal with higher intensity of the stimulating light beam, and enabling the camera not to work and not to collect images;
mode three, recording stimulation synchronization mode
And controlling the first scanning galvanometer to sample at intervals by controlling the second scanning galvanometer to be in a state on, alternately obtaining a light intensity signal with lower intensity of an imaging light beam and a light intensity signal with higher intensity of a stimulating light beam, and keeping continuously acquiring images by the camera in real time.
According to the invention, because of chromatic aberration caused by wavelength difference of the imaging light beam and the stimulating light beam, and because of the difference of the focus positions of the light beams after the light beams are introduced into the objective lens due to incomplete registration, the stimulating light beam and the imaging light beam are strictly registered in the initial xy direction by applying deflection voltage to the scanning galvanometer, and the precision is ensured.
According to the invention, by controlling the opening and closing of the two scanning galvanometers, the system can realize a single recording function, a single stimulation function and a recording stimulation synchronization function, and different experimental paradigms are realized by matching with each other.
The intensity of the signal is closely related to the power of the imaging light beam, in order to ensure the accuracy and stability of the signal in the recording process, 1 to 2 paths of the multimode fiber outlet are realized by using a 1x2 fused fiber coupler, one path is used as a monitoring path, a self-calibration component is introduced to monitor the imaging light beam and the stimulating light beam in real time, the light beam deviating from the optical axis is corrected back in a mode of finely adjusting the voltage value of the scanning galvanometer, and the stability of the system is ensured.
Experiments prove that the combination of the long-wave-band stimulating light and the short-wave-band imaging light can effectively reduce spectral interference, and the trap dichroic mirror with the corresponding wavelength is matched, so that the influence of the high-power stimulating light on the imaging light and the measuring signal light can be effectively avoided, and the real-time recording of signals in the stimulating process can be realized.
The invention can synchronously carry out optical fiber recording and optical stimulation by matching a corresponding control scheme and a self-calibration system through the structure of the double scanning galvanometers and combining the specially processed multimode optical fiber, thereby realizing the regulation and control of the brain nerve activity of the organism and the real-time monitoring of signals.
The invention has the beneficial effects that:
the invention adds the setting of light stimulation on the basis of optical fiber recording, selects a single recording mode, a single stimulation mode or a stimulation recording synchronous mode according to the condition, and correspondingly realizes two functions of brain area information reading, brain nerve activity regulation and control, and brain nerve regulation and information synchronous reading.
In addition, the end face of the multimode optical fiber is designed with an 8-degree inclined plane, and an optical coating is added, so that the end face reflection of a high-power stimulating light beam is reduced, and the transmission and collection efficiency of a nerve signal is improved.
The invention adopts the scanning galvanometer to control the stimulating light beam, the system can reach the fastest stimulating frequency of 1kHz by matching the galvanometer controller with a control program, the stimulating frequency and the stimulating time can be adjusted, and the use of the scanning galvanometer ensures the stimulating light beam and the imaging light beam and strict registration and ensures the precision.
Meanwhile, a self-calibration component is introduced to monitor the imaging light beam and the stimulating light beam in real time, so that the stability of the system is ensured. Experimental results prove that the optical stimulation regulation and control of a single optical fiber and the synchronous recording of nerve signals can be realized, the signal noise is low, and the sensitivity is high.
The invention has the advantages of experimental organism compatibility, magnetic compatibility, synchronous stimulation and recording and adjustable stimulation parameters.
Drawings
To explain the present invention in more detail, reference is made to the following description taken in conjunction with the accompanying drawings. The figure shows a system diagram of the method of the invention, listing specific elements and explaining accordingly.
FIG. 1 is a block diagram of the system architecture of the present invention.
Fig. 2 is a schematic diagram of the system of the present invention.
Fig. 3 is a timing diagram for single recording, single stimulation mode, and stimulation recording synchronization mode.
Fig. 4 is a signal recorded by the camera in the no-sample synchronous stimulus recording mode.
Fig. 5 is a record of experimental animal signals: the signal recorded by the camera in the synchronous stimulation recording mode of the experimental animal is shown in the formula (I), and the signal recorded by the camera in the single recording mode of the experimental animal is shown in the formula (II).
Fig. 6 is a graph showing experimental paradigm and experimental results combining three modes in one example.
In the figure: the device comprises a stimulus light source 1, a first half-wave plate 2, a first doublet lens 3, a second doublet lens 4, a first scanning galvanometer 5, a scanning mirror 6, an infinity correction sleeve lens 7, an imaging light source 8, a second half-wave plate 9, a second scanning galvanometer 10, a third doublet lens 11, a first reflecting mirror 12, a fourth doublet lens 13, a second reflecting mirror 14, a polarization splitting prism 15, a dichroic mirror 16, an objective lens 17, a first multimode optical fiber 18, a 1x2 fused fiber coupler 19, a second multimode optical fiber 20, a third multimode optical fiber 21, a photoelectric detector 22, an optical filter 23, a fifth doublet lens 24, a camera 25 and a galvanometer controller 26.
Detailed Description
In order to make the purpose and technical solution of the present invention clearer, the present invention is further described with reference to the accompanying drawings and specific embodiments.
As shown in fig. 1, the device comprises a recording light source module, a stimulation module, a signal acquisition module and a signal recording module.
The device comprises a recording light source module, a signal acquisition module and a control module, wherein an imaging light beam emitted by an imaging light source passes through a stimulation module and then reaches the signal acquisition module, and the power of the imaging light source is adjustable and is 0-100 microwatts;
the stimulation module sends stimulation light beams to the signal acquisition module through the stimulation light source, the power and the frequency of the stimulation light source are adjustable, the power is 0-20 milliwatt, and the frequency is 0.01-1kHz;
the device comprises a signal acquisition module, a light source module and a control module, wherein the signal acquisition module is used for receiving imaging light beams from the recording light source module and stimulating light beams from the stimulating module, inputting the imaging light beams and the stimulating light beams to neurons of a brain region of an organism by using an implanted multimode optical fiber, regulating and controlling the brain nerve activity of the organism and exciting the neurons to generate signals, and realizing real-time acquisition of brain region nerve signals of the organism and monitoring of the light source; meanwhile, the multimode optical fiber is used for collecting fluorescence generated after the imaging light beam irradiates the neuron and returning the fluorescence to the signal recording module;
the fluorescent signal acquisition system comprises a signal recording module, wherein the signal recording module receives fluorescent light from a signal acquisition module and converts the fluorescent light into an electric signal, so that the real-time recording of 0-100 frames of signals is realized.
The imaging light source emits a blue imaging beam centered at 473 nm and the stimulating light source emits a yellow stimulating beam centered at 589 nm.
As shown in fig. 2, the recording light source module includes an imaging light source 8, a second half-wave plate 9, a second scanning galvanometer 10, a third double cemented lens 11, a first reflecting mirror 12, a fourth double cemented lens 13, and a second reflecting mirror 14; the imaging light source 8, the second half-wave plate 9 and the second scanning galvanometer 10 are sequentially arranged along the same straight line optical axis, the second scanning galvanometer 10, the third double cemented lens 11 and the first reflector 12 are sequentially arranged along the same straight line optical axis, and the first reflector 12, the fourth double cemented lens 13 and the second reflector 14 are sequentially arranged along the same straight line optical axis; the imaging light source 8 emits imaging light beams, which are sequentially polarized and rotated by the second half-wave plate 9 and reflected by the second scanning galvanometer 10, transmitted by the third double-cemented lens 11, reflected by the first reflecting mirror 12, transmitted by the fourth double-cemented lens 13, reflected by the second reflecting mirror 14, then incident into the polarization beam splitter 15, and reflected by the polarization beam splitter 15 and then incident into the dichroic mirror 16 of the signal acquisition module.
In the above process, the imaging light beam is expanded by the double-cemented lens assembly composed of the third double-cemented lens 11 and the fourth double-cemented lens 13. The first scanning galvanometer 5 performs direction deflection scanning processing on the laser beam.
As shown in fig. 2, the stimulation module includes a stimulation light source 1, a first half-wave plate 2, a first doublet lens 3, a second doublet lens 4, a first scanning mirror 5, a scanning mirror 6, an infinity-corrected sleeve lens 7, and a polarization splitting prism 15; the laser source 1, the first half-wave plate 2, the first doublet 3, the second doublet 4 and the first scanning vibration mirror 5 are sequentially arranged along the same linear optical axis, the laser source 1 emits stimulating light beams, the stimulating light beams are sequentially polarized and rotated by the first half-wave plate 2, collimated and expanded by the doublet lens assembly composed of the first doublet 3 and the second doublet 4, reflected by the first scanning vibration mirror 5, transmitted by the scanning mirror 6, transmitted by the infinity correction sleeve lens 7 and then incident into the polarization beam splitter prism 15, and transmitted by the polarization beam splitter prism 15 and then incident into the dichroic mirror 16 of the signal acquisition module.
In the above process, the excimer laser beam is collimated and expanded by the double cemented lens assembly composed of the first cemented doublet 3 and the second cemented doublet 4. The direction deflection scanning processing is performed on the laser beam by the first scanning galvanometer 5.
The scanning mirror 6 is a laser scanning lens, and when the incident light angle changes relative to the optical axis of the lens, the scanning lens can also generate a flat imaging surface.
The infinity corrected sleeve lens 7 and the scan mirror 6 combine to form a telecentric system.
The polarizing beam splitter prism 15 is used to transmit the stimulating beam and reflect the imaging beam. The polarization beam splitter prism 15 is designed on a crossing light path of the imaging light beam and the stimulation light beam, the stimulation light beam penetrates through and reflects the imaging light beam, the inclined plane of the polarization beam splitter prism 15 and the imaging light beam are placed at an angle of 45 degrees, and the imaging light beam is completely overlapped with the stimulation light beam after passing through the polarization beam splitter prism 15.
The first cemented doublet 3 and the second cemented doublet 4 form a first group 4F system, the scanning mirror 6 and the infinity correction sleeve lens 7 form a second group 4F system, and the third cemented doublet 11 and the fourth cemented doublet 13 form a third group 4F system.
As shown in fig. 2, the signal acquisition module includes a dichroic mirror 16, an objective lens 17, a first multimode fiber 18, a self-calibration module, and a photodetector 22; the two output ends of the self-calibration module are respectively connected with the photoelectric detector 22 and neurons of a brain region of an organism, and the transmitted stimulating light beams and the transmitted imaging light beams are respectively incident to the photoelectric detector 22 and the neurons of the brain region of the organism through the self-calibration module;
the stimulating light beam irradiates the neuron, and can excite the photosensitive protein expressed in the neuron cell to generate selectivity on the passing of cations or anions, so that the membrane potential at two sides of the cell membrane is changed, and the aim of selectively exciting or inhibiting the cell is fulfilled;
the excitation or inhibition of the cell can cause the concentration of free calcium ions in the cell to change rapidly, and the imaging light beam irradiates the neuron, so that the calcium indicator expressed in the neuron can be excited, and the concentration of the calcium ions in the neuron can be expressed through a fluorescence signal. The fluorescence is reflected back to the dichroic mirror 16 according to the original path of the imaging light beam, and is reflected to the signal recording module to be detected and received.
The photo detector 22 employs a photodiode, and when receiving the light intensity signal, the photo detector displays a corresponding photo current value at the receiving end.
The self-calibration assembly comprises a 1x2 fused fiber coupler 19, a second multimode fiber 20 and a third multimode fiber 21; one bundling end of the 1x2 fused fiber coupler 19 is used as an input end of a self-calibration component and is connected with the other end of the first multimode fiber 18, and two branch ends of the 1x2 fused fiber coupler 19 are respectively connected with the photoelectric detector 22 and neurons in a brain region of an organism through the second multimode fiber 20 and the third multimode fiber 21.
The stimulating light beam and the imaging light beam are divided into two beams after being split into two beams by the light intensity of the 1x2 fused fiber coupler 19, and the two beams are respectively incident to the photoelectric detector 22 and the neuron of the brain area of the organism to be connected.
When the stimulating beam and the imaging beam are subject to errors such as drift of mechanical parts, the back focal position of the objective lens 17 is shifted, thereby affecting the efficiency of coupling the stimulating beam and the imaging beam into the first multimode optical fiber 18. At this time, the photodetector 22 recognizes the power drop of the exit end of the third multimode optical fiber 21, the photodetector 22 converts the light intensity signal into an electrical signal, and the galvanometer controller 26 changes the angle of the mirror in the first scanning galvanometer 5 or the second scanning galvanometer 10 according to the electrical signal. When the light intensity signal recognized by the photodetector 22 reaches a target value, the focal point of the light beam behind the objective lens 17 is located at the center of the end face of the first multimode optical fiber 18, and the coupling efficiency is highest.
Or when the hardware clock is unstable, the actual stimulation frequency and the set frequency have deviation. The photodetector 22 feeds this frequency signal back to the galvanometer controller 26, which changes the frequency of the applied signal to the galvanometer until the frequency of the stimulating beam collected by the photodetector 22 in real time reaches a target value.
The 1x2 fused fiber coupler 19 is used for splitting a light beam emitted from the first multimode fiber 18 into two parts, the two parts are incident on the second multimode fiber 20 and the third multimode fiber 21, the second multimode fiber 20 is connected with neurons in a brain region of an organism, and the third multimode fiber 21 is connected with the photoelectric detector 22, so that real-time monitoring and feedback of signals in an experimental process are guaranteed.
The intensity of the signal is closely related to the power of the imaging light beam, and the accuracy and stability of the signal in the recording process can be guaranteed through the self-calibration component.
As shown in fig. 2, the signal recording module includes an optical filter 23, a fifth doublet lens 24, and a camera 25; the optical filter 23, the fifth doublet 24 and the camera 25 are sequentially arranged along the same straight optical axis, and the fluorescence coming from the signal acquisition module is incident into the camera 25 after being sequentially filtered by the optical filter 23 and converged by the fifth doublet 24, and is detected and acquired by the camera 25.
The first multimode optical fiber 18, the second multimode optical fiber 20 and the third multimode optical fiber 21 are all multimode optical fibers with the diameter of 200 microns and the numerical aperture of 0.37.
The filter 19 has a transmission bandwidth of 20 nm, an OD of 4 and a center wavelength of 515 nm.
The fiber end faces of the first multimode fiber 18, the second multimode fiber 20 and the third multimode fiber 21 are designed with 8-degree inclined planes and optical coating is added, so that the end face reflection of high-power stimulation beams is reduced, and the signal transmission and collection efficiency is improved.
The optical fiber stimulation device further comprises a galvanometer controller 26 which is respectively and electrically connected with the second scanning galvanometer 10 of the recording light source module, the first scanning galvanometer 5 of the stimulation module and the photoelectric detector 22 of the signal acquisition module, so that the photoelectric detector 22 is connected with the first scanning galvanometer 5 and the second scanning galvanometer 10 through the galvanometer controller 26 to send real-time feedback signals, the galvanometer controller 26 acquires electric signals detected by the photoelectric detector 22 in real time, and the feedback adjustment is carried out on the work of the second scanning galvanometer 10 of the recording light source module and the first scanning galvanometer 5 of the stimulation module.
When the power and frequency of the stimulating light beam change, the light intensity of the stimulating light beam is collected in real time by the photoelectric detector 22 and converted into an electric signal, and the mirror angle in the first scanning galvanometer 5 is changed by the galvanometer controller 26 according to the electric signal control until the light intensity of the stimulating light beam collected in real time by the photoelectric detector 22 reaches a target value;
when the power and frequency of the imaging light beam change, the light intensity of the imaging light beam collected by the photodetector 22 in real time is converted into an electrical signal, and the galvanometer controller 26 changes the angle of the mirror in the second scanning galvanometer 10 according to the electrical signal until the light intensity of the imaging light beam collected by the photodetector 22 in real time reaches a target value.
The galvanometer controller adopts a signal acquisition card, receives an optical signal from the photoelectric detector and applies the calibrated galvanometer voltage value to the scanning galvanometer.
An optical axis of an objective lens 17 perpendicular to the signal acquisition module is taken as a detection plane, and an x direction and a y direction which are perpendicular to each other and orthogonal are established on the detection plane:
the first scanning galvanometer 5 adopts a one-dimensional galvanometer system to adjust the x direction and is used for deflecting the thorn laser beam in the x direction to realize light stimulation with different frequencies and time;
the second scanning galvanometer 10 adopts a two-dimensional galvanometer system, adjusts the x direction and the y direction, and is used for deflecting the imaging light beam in the x direction and the y direction to realize light imaging.
The imaging beam and the stimulating beam are corrected to be completely overlapped with the stimulating beam due to the color difference caused by the wavelength difference and the position difference of a focus point caused by the incomplete registration of the beams. In the calibration of the system, the stimulation beam is first calibrated. The first galvanometer scanner 5 is applied with voltage until the light intensity value identified by the photoelectric detector 22 reaches the maximum value, and at the moment, the coupling efficiency of the stimulating light beam with the first multimode optical fiber 18 after passing through the objective lens 17 reaches the maximum value. The applied voltage of the first scanning mirror 5 at this time is set as the deflection voltage value in the state on. When the imaging light beam is calibrated, the first scanning galvanometer 5 applies the calibrated deflection voltage to enable the first scanning galvanometer to be in the state on, the imaging light beam passes through the polarization beam splitter 15 by fine adjustment of the lens angle of the second scanning galvanometer 10, and then is strictly registered with the stimulation light beam in the xy direction, so that the two paths of light exit objective lens rear focusing positions are strictly aligned, and the voltage value applied by the second scanning galvanometer 10 at the moment is used as the deflection voltage value of the second scanning galvanometer 10 in the state on. In subsequent experiments, the stimulation, imaging or synchronous stimulation imaging of the neurons of the brain region of the organism at the emergent position of the second multimode optical fiber 20 is realized by applying the calibrated deflection voltage to the first scanning galvanometer 5 and the second scanning galvanometer 10 respectively or simultaneously.
Three different modes of the system are constructed by switching on and off of two different states of the first scanning galvanometer 5 and switching on and off of two different states of the second scanning galvanometer 10:
mode one, single recording mode
Controlling the first scanning galvanometer 5 to be in an off state and the second scanning galvanometer 10 to be in an on state, controlling the photoelectric detector 22 to sample at intervals to obtain a light intensity signal with lower intensity of an imaging light beam, and keeping the camera 25 to continuously acquire images in real time; only signal reading and recording functions are realized.
Mode two, single stimulation mode
Controlling the first scanning galvanometer 5 to be in a state on and the second scanning galvanometer 10 to be in a state off, controlling the photoelectric detector 22 to sample at intervals to obtain a light intensity signal with higher intensity of the stimulating light beam, and controlling the camera 25 not to work and not to collect images; only the light stimulation regulation function of brain information is realized.
Mode three, recording stimulation synchronization mode
The first scanning galvanometer 5 is controlled to be in the state on and the second scanning galvanometer 10 is controlled to be in the state on, the photoelectric detector 22 is controlled to alternately sample at intervals, a light intensity signal with lower intensity of the imaging light beam and a light intensity signal with higher intensity of the stimulating light beam are obtained, the camera 25 keeps continuously collecting images in real time, and the brain information light stimulation regulation and control function and the brain information synchronous recording function are achieved.
The first galvanometer scanner 5 has two switching states:
when extra voltage is applied to the first scanning galvanometer 5, the state is on, the first scanning galvanometer 5 controls the stimulating light beam to propagate along the optical axis, the stimulating light beam is coupled into the first multimode optical fiber 18 through the objective lens 17 and is emitted to the neuron from the second multimode optical fiber 20 for stimulation;
when no extra voltage is applied to the first scanning galvanometer 5, the state is off, and the first scanning galvanometer 5 controls the stimulation light beam to deviate from the optical axis, so that the focus of the light beam which passes through the objective lens 17 deviates from the end face of the input end of the first multimode optical fiber 18 and cannot be emitted to a neuron from the second multimode optical fiber 20 for stimulation;
the first scanning mirror 5 is controlled to switch between a state on and a state off to form a stimulating light beam of a frequency.
The second scanning galvanometer 10 has the following two switch states:
when no extra voltage is applied to the second scanning galvanometer 10, the state is on, the second scanning galvanometer 10 controls the imaging light beam to propagate along the optical axis, the imaging light beam is coupled into the first multimode fiber 18 through the objective lens 17, and the imaging light beam is emitted from the second multimode fiber 20 to a neuron to be excited to generate fluorescence for imaging;
when extra voltage is applied to the second scanning galvanometer 10, the state is off, and the imaging light beam is controlled by the second scanning galvanometer 10 to deviate from the optical axis, so that the focus of the light beam transmitted through the objective lens 17 deviates from the end face of the input end of the first multimode optical fiber 18 and cannot be emitted from the second multimode optical fiber 20 to a neuron for excitation imaging.
The examples of the invention are as follows:
in this example, experimental animal mice were used to excite light sensitive proteins expressed by neurons in specific brain regions of the mice and to read fluorescent signals generated during neural activity. Neurons express the light sensitive protein halophilic bacteriorhodopsin (NpHR), which inhibits neuronal activity under yellow light stimulation. The neuron expresses calcium indicator GCaMP6, can be excited by blue light to generate fluorescence, and can observe and record the neuron activity in real time.
Referring to fig. 3, the system has three modes, wherein the mode one is a single recording mode, the mode two is a single stimulation mode, and the mode three is a recording stimulation synchronization mode. The switching of the first mode, the second mode and the third mode can be realized by setting the alternating frequency and the duration of the on state and the off state of the first scanning galvanometer and the second scanning galvanometer, so that different stimulation normal forms are formed, and the embodiment adopts the stimulation normal form that the single stimulation time is 5 milliseconds, the stimulation frequency is 20Hz, the total stimulation time is 5 seconds, and the stimulation stop time is 15 seconds. During each 5 second stimulation cycle, the first galvanometer scans the stimulation beam into the multimode optical fiber 18 for a 5 millisecond dwell, scans out of the multimode optical fiber 18 for a 45 millisecond dwell, and forms a stimulation beam having a frequency of 20 Hz.
Referring to fig. 4, in the no-sample synchronous stimulation recording mode, the signal recorded by the camera 25 is flat, which indicates that no crosstalk of the stimulation beam to the signal occurs.
Referring to fig. 5, the present embodiment employs a stimulation paradigm of a single stimulation time of 5 milliseconds, a stimulation frequency of 20Hz, a total stimulation duration of 5 seconds, and a rest stimulation duration of 15 seconds. The synchronous stimulus recording signal is shown in fig. 5 (i). The stimulation module is turned off, and the signal recorded by the experimental animal is shown in (II) of figure 5. Therefore, the invention can realize synchronous stimulation and recording of a single optical fiber, realize brain nerve activity regulation and control and brain information synchronous reading, and has good signal quality and adjustable stimulation parameters.
Referring to fig. 6, this example shows an experimental paradigm combining three modes and corresponding experimental results. In this example, the experimental objective was to perform the manipulation of mouse motor behavior and the corresponding signal recording to study the function of the mouse motor brain region.
During the experiment, first, using mode one: and in a single recording mode, the monitoring of the quality of the mouse fluorescence signal is completed, and whether the calcium indicator is expressed in the neuron cells or not is judged. The third use mode: and (3) a stimulation recording synchronous mode is adopted, the quality monitoring of a mouse stimulation signal is completed, and whether the photosensitive protein is expressed in the neuron cells or not is judged. When the light sensitive protein is expressed, the subsequent experiment can be started.
In the formal experiment, mode two was used: and in the single stimulation mode, the mouse movement behavior in the stimulation process is analyzed by shooting videos, and the movement function specifically controlled by the optical fiber implanted brain area is judged.
The calcium ion indicator is sensitive to illumination, and continuous illumination can cause photobleaching of the calcium ion indicator, so that the calcium ion indicator cannot emit fluorescence or the fluorescence is weakened, and the accuracy of an experimental result is influenced.
During the experiment, a brief pattern one was performed at 5min intervals: and a single recording mode is used for judging whether photobleaching influences mouse neuron signals and influences experimental results. When the signal value was lower than expected, the experiment was stopped. A third brief mode is performed simultaneously: the synchronous mode of stimulation and recording aims to judge whether the photosensitive protein loses activity or the activity is weakened and whether the cells are effectively activated by the stimulation laser beam. Also, when the signal value was lower than expected, the experiment was stopped.
The operation mode effectively avoids the influence of continuous imaging light beams on biological signals and avoids the damage of heat generated by long-time light beams on biological tissues.
Claims (6)
1. A brain neural activity regulation and control and brain information synchronous reading system is characterized in that:
the device comprises a recording light source module, a signal acquisition module and a control module, wherein an imaging light beam emitted by an imaging light source passes through a stimulation module and then enters the signal acquisition module;
the recording light source module comprises an imaging light source (8), a second half-wave plate (9), a second scanning galvanometer (10), a third double-cemented lens (11), a first reflecting mirror (12), a fourth double-cemented lens (13) and a second reflecting mirror (14); the imaging light source (8), the second half-wave plate (9) and the second scanning galvanometer (10) are sequentially arranged along the same straight line optical axis, the second scanning galvanometer (10), the third double cemented lens (11) and the first reflector (12) are sequentially arranged along the same straight line optical axis, and the first reflector (12), the fourth double cemented lens (13) and the second reflector (14) are sequentially arranged along the same straight line optical axis; an imaging light source (8) emits imaging light beams, the imaging light beams are subjected to polarization rotation through a second half-wave plate (9) and reflection through a second scanning galvanometer (10) in sequence, then are transmitted through a third double-cemented lens (11), reflected through a first reflecting mirror (12), transmitted through a fourth double-cemented lens (13) and reflected through a second reflecting mirror (14), and then are incident into a polarization beam splitter prism (15), and are incident into a signal acquisition module after being reflected through the polarization beam splitter prism (15);
the stimulation module sends out stimulation light beams to the signal acquisition module through a stimulation light source;
the stimulation module comprises a stimulation light source (1), a first half-wave plate (2), a first doublet cemented lens (3), a second doublet cemented lens (4), a first scanning galvanometer (5), a scanning mirror (6), an infinity correction sleeve lens (7) and a polarization splitting prism (15); the laser source (1), the first half-wave plate (2), the first doublet cemented lens (3), the second doublet cemented lens (4) and the first scanning vibration mirror (5) are sequentially arranged along the same linear optical axis, the laser source (1) emits stimulating light beams, the stimulating light beams are sequentially subjected to polarization rotation through the first half-wave plate (2), a doublet cemented lens component formed by the first doublet cemented lens (3) and the second doublet cemented lens (4) is subjected to beam expanding and collimation, and the first scanning vibration mirror (5) reflects the stimulating light beams, and then are sequentially subjected to transmission through the scanning mirror (6), transmission through the infinity correction sleeve lens (7), incidence into the polarization beam splitter prism (15), and incidence into the signal acquisition module after transmission through the polarization beam splitter prism (15);
the device comprises a signal acquisition module, a light source module and a control module, wherein the signal acquisition module is used for receiving imaging light beams from the recording light source module and stimulating light beams from the stimulating module, inputting the imaging light beams and the stimulating light beams to neurons of a brain region of an organism by using an implanted multimode optical fiber, regulating and controlling the brain nerve activity of the organism and exciting the neurons to generate signals, and realizing real-time acquisition of brain region nerve signals of the organism and monitoring of the light source; meanwhile, the multimode optical fiber is used for collecting fluorescence generated after the imaging light beam irradiates the neuron and returning the fluorescence to the signal recording module;
the fluorescent light detector comprises a signal recording module, a fluorescence detection module and a signal processing module, wherein the signal recording module receives fluorescence from a signal acquisition module and converts the fluorescence into an electric signal;
the signal acquisition module comprises a dichroic mirror (16), an objective lens (17), a first multimode fiber (18), a self-calibration module and a photoelectric detector (22); the device comprises a dichroic mirror (16), an objective lens (17), a first multimode fiber (18) and a self-calibration module, wherein the dichroic mirror (16), the objective lens (17), the first multimode fiber (18) and the self-calibration module are sequentially arranged along the same straight line optical axis, stimulating light beams and imaging light beams are incident into the dichroic mirror (16) through a polarization beam splitter prism (15) of the stimulating module to be transmitted, and then are incident into one end of the first multimode fiber (18) after being transmitted and converged through the objective lens (17), the other end of the first multimode fiber (18) is connected with the input end of the self-calibration module, the two output ends of the self-calibration module are respectively connected with a photoelectric detector (22) and neurons in a brain region of an organism, and the stimulating light beams and the imaging light beams after being transmitted are incident into the photoelectric detector (22) and the neurons in the brain region of the organism through the self-calibration module;
the self-calibration module comprises a 1x2 fused fiber coupler (19), a second multimode fiber (20) and a third multimode fiber (21); one bundling end of the 1x2 fused fiber coupler (19) is used as an input end of a self-calibration module and is connected with the other end of the first multimode fiber (18), and two branch ends of the 1x2 fused fiber coupler (19) are respectively connected with the photoelectric detector (22) and neurons in a brain region of an organism through the second multimode fiber (20) and the third multimode fiber (21);
three different modes of the system are constructed by combining the on and off switching of two different states of the first scanning galvanometer (5) and the on and off switching of two different states of the second scanning galvanometer (10):
mode one, single recording mode
Under the control of the first scanning galvanometer (5) in an off state and the second scanning galvanometer (10) in an on state, the photoelectric detector (22) is controlled to sample at intervals to obtain a light intensity signal with lower intensity of an imaging light beam, and the camera (25) keeps continuously acquiring images in real time;
mode two, single stimulation mode
Controlling the first scanning galvanometer (5) to be in a state on and the second scanning galvanometer (10) to be in a state off, controlling the photoelectric detector (22) to sample at intervals to obtain a light intensity signal with higher intensity of the stimulating light beam, and controlling the camera (25) not to work and not to collect images;
mode three, recording stimulation synchronization mode
And controlling the first scanning galvanometer (5) to be in a state on and the second scanning galvanometer (10) to be in a state on, controlling the photoelectric detector (22) to sample at intervals, alternately obtaining a light intensity signal with lower intensity of an imaging light beam and a light intensity signal with higher intensity of a stimulating light beam, and keeping the camera (25) to continuously acquire images in real time.
2. The system for regulating brain nerve activity and synchronously reading brain information according to claim 1, wherein: the imaging light source emits imaging light beams with the central wavelength of 473 nanometers, and the stimulating light source emits stimulating light beams with the central wavelength of 589 nanometers.
3. The system for regulating brain nerve activity and synchronously reading brain information according to claim 1, wherein: the signal recording module comprises an optical filter (23), a fifth double-cemented lens (24) and a camera (25); the optical filter (23), the fifth double-cemented lens (24) and the camera (25) are sequentially arranged along the same straight line optical axis, and the fluorescence coming from the signal acquisition module is sequentially filtered by the optical filter (23), converged by the fifth double-cemented lens (24) and then enters the camera (25) to be detected and acquired by the camera (25).
4. The system for regulating brain nerve activity and synchronously reading brain information according to claim 1, wherein: the optical fiber end faces of the first multimode optical fiber (18), the second multimode optical fiber (20) and the third multimode optical fiber (21) are designed with 8-degree inclined planes and added with optical coatings.
5. The system for regulating brain nerve activity and synchronously reading brain information according to claim 1, wherein: the stimulation light source module is characterized by further comprising a galvanometer controller (26) which is respectively electrically connected with the second scanning galvanometer (10) of the recording light source module, the first scanning galvanometer (5) of the stimulation module and the photoelectric detector (22) of the signal acquisition module, wherein the galvanometer controller (26) acquires electric signals detected by the photoelectric detector (22) in real time and carries out feedback adjustment on the work of the second scanning galvanometer (10) of the recording light source module and the first scanning galvanometer (5) of the stimulation module.
6. The system for regulating brain neural activity and synchronously reading brain information as claimed in claim 1, wherein: an optical axis of an objective lens (17) which is vertical to the signal acquisition module is taken as a detection surface, and an x direction and a y direction which are vertical and orthogonal to each other are established on the detection surface:
the first scanning galvanometer (5) adjusts the x direction and is used for deflecting the stimulating laser beam in the x direction to realize light stimulation with different frequencies and time;
the second scanning galvanometer (10) adjusts the x direction and the y direction and is used for deflecting the thorn laser beam in the x direction and the y direction to realize optical imaging.
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